The mammalian female reproductive tract, including the oviducts, uterus, and vagina, is essential for the continuation of the species and a frequent site of human disease, including infertility and cancer. The female reproductive tract is derived from the M[unreadable]llerian ducts of the fetus, a pair of epithelial tubes with a surrounding mesenchyme. In mammals, two pairs of genital ducts form within the mesonephroi associated with the fetal gonads regardless of sex genotype. Initially, the Wolffian ducts form that subsequently give rise to the vas deferentia, epididymides, and seminal vesicles. The Wolffian ducts then guide the formation of the M|llerian ducts. In males, the fetal testes produce the TGF-b family member anti-M[unreadable]llerian hormone (AMH) that binds receptors expressed in the M[unreadable]llerian duct mesenchyme, causing the elimination of the M[unreadable]llerian ducts. The fetal ovaries do not produce AMH, permitting M[unreadable]llerian duct differentiation. Thus, mammalian fetuses are initially ambi-sexual with the potential to develop both male and female reproductive tract organs. Defects in the formation of the genital ducts and resolution of the ambi-sexual state to a male or female phenotype lead to disorders of sexual development (DSD). Although much progress has been made in understanding the development and differentiation of the female reproductive tract and the elimination of the M[unreadable]llerian system in the male fetus there are still many fundamental unanswered questions. The primary objective of this proposal is to determine the molecular, cellular, and developmental mechanisms that regulate female reproductive tract organogenesis and its regression during male differentiation. PUBLIC HEALTH RELEVANCE: The mammalian female reproductive tract, including the oviducts, uterus, and vagina, is essential for the continuation of the species and an important site for human disease, notably infertility and cancer. Surprisingly, relatively little is known about the developmental genetics of female reproductive tract formation. The primary objective of this proposal is to determine the molecular, cellular, and developmental mechanisms that regulate female reproductive tract organogenesis and its regression during male differentiation.